The specific aims of this project are designed to better understand the biology and virulence of Aspergillus fumigatus, the causative agent of invasive aspergillosis (IA), the host immune response, and the role of iron in the interaction between fungus and host. IA is an understudied disease of growing significance worldwide that causes over 3,500 annual deaths in the U.S. alone. The significance of IA is growing due to substantial increases in the number of allogenic and autologous stem cell transplants, as well as advances in medical technologies that are expanding the spectrum of patients susceptible to A. fumigatus infections. For example, while transplant patients remain the patient population most at risk, immunosuppression therapies are now routinely used to treat more common diseases including, asthma, rheumatoid arthritis, and gastrointestinal disorders. With the rising number of immunocompromised patients, the significance of invasive infections caused by A. fumigatus and other invasive moulds will undoubtedly continue to increase. In order to identify new and promising therapeutic targets to treat infection with this ubiquitous fungus, researchers have incorporated a systems biology approach to understand the fungal pathways contributing to virulence. The project proposed here applies this approach to the host response, a step toward the ultimate goal of integrating host and fungal pathways. While the host response is multi-pronged, a central factor in the interplay between the host and A. fumigatus is the manipulation of iron levels in both macrophages and epithelial cells. Iron homeostasis is regulated by a control system of proteins that are connected through several intertwined feedback loops. This complicates an understanding of the mechanisms that mediate the effect of cytokine production on iron levels. The focus of the proposed project is to elucidate the network of immune proteins and key proteins involved in iron homeostasis in both alveolar macrophages and lung epithelial cells, with the goal of identifying key drivers of iron regulation during Aspergillus infection. Th central discovery tool in the project will be a dynamic mathematical model of the network to be constructed that encodes the dynamic response and the effect of feedback loops under perturbations of key proteins.